Colorectal cancer (CRC) mortality remains a leading cause of cancer deaths in the United States underscoring the need for effective chemoprevention strategies. Number of agents have demonstrated chemopreventive efficacy in experimental models. However, clear clinical evidence has been lacking secondary to large number of patients that need long term monitoring for prevention endpoints. Intermediate biomarkers have been advocated, but most conventional markers are either insensitive or have suboptimal positive predictive value for colon carcinogenesis. Thus, discovering an easily detectable sensitive and accurate intermediate biomarker for colon carcinogenesis will be an incredible clinical tool in designing and testing new chemopreventive therapies. Ideally, such biomarker(s) would quantitatively assess the efficacy of a chemopreventive strategy early in the course of the therapy, which is of great benefit to patients, drug developers, and biomedical researchers. In this study, we propose to bridge the advances of optical spectroscopy and imaging to those of molecular biology in order to establish light scattering spectroscopy (LSS) in identifying micro/nanoscale ultrastructural signatures of the uninvolved colonic epithelium as accurate intermediate biomarker for chemoprevention of colon cancer. Our group has utilized LSS to accurately detect dysplastic changes in number of organs including colon and were the first to characterize the earliest pre-cancerous transformations in colon cancer. LSS can be used to probe tissue structures ranging from few nanometers to several micrometer. Our preliminary data in experimental colon carcinogenesis strongly suggests that altered LSS signatures occur far earlier than the any classic genetic or cellular events. Moreover, using human colon cancer cell lines, we have shown that chemopreventive agents rapidly modulate LSS signatures far before detection of any other changes by conventional methods. We, therefore, hypothesize that LSS will provide sensitive and responsive intermediate biomarkers for chemoprevention of colon carcinogenesis. In this study, using AOM-model of cancer, we will identify LSS signatures modulated by progression or prevention of cancer. One of the long term outcomes of this project would be to develop a novel technique to risk stratify patients for colon neoplasia, monitor chemopreventive strategies, and to non-invasively diagnose colon and potentially other cancers.